Scientists have long known that DEET, the gold standard of insect repellents for more than six decades, effectively repels mosquitoes, but now researchers in the Walter Leal Lab at the University of California, Davis, have discovered the exact odorant receptor that makes DEET effective. They have also identified a plant defensive compound that might mimic DEET, a discovery that could pave the way for better and more affordable insect repellents.

Dr. Walter Leal, Co-Chair of the 2016 International Congress of Entomology, and colleagues in his lab published groundbreaking research in 2008 in the Proceedings of the National Academy of Sciences that found that mosquitoes avoid DEET because they dislike the smell, not because it masks the smell of the host or jams the senses.

“Mosquitoes don’t like it because it smells bad to them,” Leal said at the time.

Now Leal and his team — project scientist Pingxi Xu, postdoctoral scholar Young-Moo Choo, and agricultural and environmental chemistry graduate student Alyssa De La Rosa — have published new research in the Proceedings of the National Academy of Sciences.

The team examined the receptors of the southern house mosquito, Culex quinquefasciatus, which transmits diseases such as West Nile virus. Mosquitoes detect DEET and other smells with their antennae. The researchers set out to investigate two hypotheses regarding DEET’s mode of action: activation of ionotropic receptor IR40a vs. odorant receptor(s).

“Ionotropic receptor is another family of olfactory receptors, which seems to be the ancestral version when insects were aquatic,” Leal said. “So, the ionotropic receptors normally detect acid, bases, and other water soluble compounds.”

They discovered that the direct activation of an odorant receptor, not an ionotrophic receptor, “is necessary for DEET reception and repellency in Culex mosquitoes.” They also detected a link between DEET and methyl jasmonate, thus suggesting that DEET might work by mimicking a defensive compound from plants.

“Vector-borne diseases are major health problems for travelers and populations living in endemic regions,” said Leal. “Among the most notorious vectors are mosquitoes that unwittingly transmit the protozoan parasites causing malaria and viruses that cause infections, such as dengue, yellow fever, chikungunya, and encephalitis.”

According to Dr. Leal, diseases transmitted by mosquitoes destroy more lives annually “than war, terrorism, gun violence, and other human maladies combined. Every year, malaria decimates countless lives — imagine a city of San Francisco perishing to malaria year after year. The suffering and economic consequences in endemic areas are beyond imagination for those living in malaria-free countries. Both natives and visitors to endemic areas want to keep these ‘infected needles’ at bay. In the absence of vaccines for malaria, dengue, and encephalitis, one of the most ancient and effective prophylactic measures against mosquito-borne diseases is the use of DEET.”

Dan Strickman of the Bill and Melinda Gates Foundation, who is not involved in the study, praised the work.

“We are at a very exciting time for research on insect repellents,” said Strickman. “For decades, the field concentrated on screening compounds for activity, with little or no understanding of how chemicals interacted with mosquitoes to discourage biting. Use of modern techniques that combine molecular biology, biochemistry, and physiology has generated evidence on how mosquitoes perceive odors.”

Strickland said the paper makes “a convincing case” that the principal active ingredients in repellents activate a particular odorant receptor in mosquitoes. The same receptor, Strickland noted, is activated by a naturally occurring plant defensive compound, “suggesting that synthetic repellents take advantage of the same mechanisms that plants have developed as a result of selection exerted by herbivorous insects.”

Strickland called the research “a fascinating biological story, but it also opens the door to systematic development of highly effective repellents that would create a big improvement in personal protection. In theory, a compound that was 100,000 times more effective than current repellents might be used at much lower concentration and create completely new ways to prevent mosquito bites.”

Zoologist Paul Weldon of the Smithsonian’s Conservation Biologist Institute, who also is not involved in the study, said, “Since DEET is strictly synthetic and not a natural product, it has been challenging to understand the adaptive nature of the response it elicits. It is not as if the compound emanates from, say, spider webs or fishy water, where avoidance by mosquitoes would make sense. [These researchers] have solved the mystery of where the DEET response comes from: it is in response to plant chemical defenses. This, by the way, also explains why the DEET response is widespread, occurring in many arthropods, including those that are not ectoparasitic — like cockroaches. The repellence of other arthropods by DEET may have tipped off some of those investigating the DEET response, but I’m not sure that it did. The focus of research on DEET seems to have been with the organisms in which it just so happened to be discovered — mosquitoes. [This] study suggests that there is a much broader array of DEET-sensitive organisms than previously suspected. No doubt, this finding will assist further investigations of it.”

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Informative and a cardinal finding in insect repellent research. The research has provided much insights into the target site of DEET, in insects. It has given researchers, in this area of insect management, the ability to look for similar sites and experiment with other types of compounds.

“DEET might work by mimicking a defensive compound from plants” and “[These researchers] have solved the mystery of where the DEET response comes from: it is in response to plant chemical defenses.”
I can see how plant chemical defenses would deter an herbivore, but I wonder why a mosquito would be repelled. This makes the mystery of where the DEET response comes from even more mysterious to me.
I wonder if there is another interpretation of the results from this study…